BERKELEY, CA — The National Institute of General
Medical Sciences (NIGMS) has launched the "Protein Structure
Initiative" with the intent to determine the form and function of
thousands of proteins over the next decade. The initial phase of this
initiative has started with the awarding of seven new grants, each
totaling around $4 million for the first year, including one to Sung-Hou
Kim, a chemist who heads the Structural Biology Department of the Physical
Biosciences Division at the U.S. Department of Energy's Lawrence Berkeley
National Laboratory (Berkeley Lab).

"This project can be viewed as an inventory of all the protein
structure families that exist in nature," said Dr. Marvin Cassman,
NIGMS Director, in announcing the grants. "We expect that this effort
will yield major biological findings that will improve our understanding
of health and disease."

Cassman said his agency, which is one of the components of the National
Institutes of Health, expects to spend approximately $150 million on these
inaugural seven grants over the next five years. This would make NIGMS the
single largest funding agency of structural genomics, the emerging
scientific field in which the identification of gene-coding DNA sequences
are combined with 3-D structural images to determine protein functions.

Said John Norvell, director of the NIGMS Protein Structure Initiative,
"These research centers are true pilots. Each will include every
experimental and computational task of structural genomics and will
develop strategies for use in the subsequent large-scale research
networks. By the fifth year of the award, we expect each pilot center to
reach a production level of 100 to 200 protein structures annually, which
is significantly greater than the current rate of protein structure
determination."

Sung-Hou Kim, who in addition to his Berkeley Lab appointment is also a
professor with the College of Chemistry at the University of California's
Berkeley campus, is a world authority on protein crystallography. He has
been a pioneer in structural genomics and one of the leading advocates for
grouping proteins into families on the basis of recurring structural
patterns known as "folds," and using these fold families to help
predict protein functions.

Other leaders working with Kim on this project include Paul Adams,
Steve Brenner, Thomas Earnest, Rosalind Kim, and David Wemmer, of Berkeley
Lab, plus Clyde Hutchison of the University of North Carolina, and David
McKay of Stanford.

With the completion of a "working draft" of the human genome,
scientists are now busy identifying the genes within the sequences of
those three billion DNA bases. The next step is to determine the purpose
of those genes, which means determining the molecular and cellular
functions of the proteins they code for. Proteins are the building blocks
of living cells and control much of the biochemical processes that are
vital to all life.

The prevailing method for predicting a protein's function is to compare
the sequence pattern of its DNA to the DNA sequence patterns of genes
whose functions have already been identified. A major problem to relying
exclusively on this approach is that while proteins in different organisms
may have similar form and function (the two go hand-in-hand for proteins),
the DNA sequencing patterns of their genes may be dramatically different.

As an alternative or supplemental approach, Kim and other
crystallography leaders have proposed that the molecular functions of a
protein can also be predicted from the folds that underlie all protein
architecture. While the number of different proteins may number in the
hundreds of thousands, most biologists agree there are probably less than
ten thousand distinctly different types of folds and that a majority if
not all proteins will belong to one of these fold families.

Under the protein structure initiative being launched by NIGMS, the
seven grant recipients will each work with representative protein
populations obtained from organisms whose entire genomes have been
sequenced. The idea being that through the eons, families of proteins have
selectively evolved into the structural shapes best suited to do their
specific jobs. Kim and his group will work with two closely related
bacteria, Mycoplasma genitalium and Mycoplasma pneumoniae.
The former contains the smallest known genome of any free-living organism
and infects the human genital and respiratory tracts. The latter causes a
form of pneumonia.

To identify the structures of the full complement of proteins that make
up these two "minimal organisms," Kim and his colleagues will
primarily use x-ray crystallography, backed by nuclear magnetic resonance
and computation. In x-ray crystallography, a beam of x-rays is sent
through a protein's crystal. The crystal's atoms cause the incoming
photons to be scattered, creating a diffraction pattern that computers can
translate into a 3-D image of the protein's structure. Kim and his
colleagues will have access to the Berkeley Center for Structural Biology
which features one of the world's premier x-ray beamlines for protein
crystallography at Berkeley Lab's Advanced Light Source (ALS).

The ALS is an electron synchrotron that produces beams of x-rays and
ultraviolet light for scientific research, which are a hundred million
times brighter than those from the best x-ray tubes. This high brightness
reduces the time required to collect a complete set of data for a single
protein from what had once been months or even years using an x-ray tube,
to a matter of weeks, days, or even hours.

"The use of a synchrotron radiation source such as the ALS can
dramatically decrease the time required to solve novel protein
structures," Kim has said. "It makes a clear and compelling case
that protein crystallography can provide a foundation for structural
genomics."

As a major part of their effort, Kim and his collaborators will look to
reduce the time required to produce and set protein crystals up in the
beamline, illuminate them with x-rays, and collect the data. Automation of
the entire process, including the use of a unique crystal-growing robotic
system designed and built by a team of engineers and technicians led by
Joe Jaklevic with Berkeley Lab's Engineering Division, will be a key.

The project will also benefit from automation tools being developed and
built to increase the throughput and efficiency of the structural
determination process, including robotic crystal mounting and alignment
and expert computation systems.

Data collected by Kim and his collaborators, along with that collected
by the other NIGMS grant recipients is to form the foundation of a public
resource linking sequence, structural, and functional information. NIGMS
will make this information be available on the Internet to all scientists.

Berkeley Lab is a U.S. Department of Energy national laboratory located
in Berkeley, California. It conducts unclassified scientific research and
is managed by the University of California.